In pharmaceutical and laboratory research and development, it is commonplace, during formulation development, stability determination, analytical method development, quality control, or otherwise, to ascertain the rate at which a solid dissolves under certain well-defined conditions and/or to predict how it will dissolve in the human system. By way of example, detailed procedures for conducting such testing and specifications for the apparatus employed therein are outlined in the publications of the American Pharmaceutical Association's Drug Standards Laboratory, the United States Pharmacopoeia (“USP”) and the National Formulary. By way of further example, USP 25 <711> Dissolution, which is incorporated herein by reference, describes a test to determine compliance with the dissolution requirements that are stated in the individual monograph for a particular drug. The current USP specifies two alternative apparatuses to be used for the test.
Apparatus 1 (or type 1 apparatus) consists of a vessel made of glass or other inert transparent materials with one of the following dimensions and capacities: for a nominal capacity of 1 liter, the height is 160 mm to 210 mm and its inside diameter is 98 mm to 106 mm; for a nominal capacity of 2 liters, the height is 280 mm to 300 mm and its inside diameter is 98 mm to 106 mm; and for a nominal capacity of 4 liters, the height is 280 mm to 300 mm and its inside diameter is 145 mm to 155 mm. Its sides are flanged at the top. The apparatus further consists of a motor, a metallic drive shaft and a cylindrical basket. See FIG. 17. It is specified that the shaft and basket components of the stirring element are fabricated of stainless steel, type 316 or equivalent, to the specifications shown in FIG. 1 of the USP. It is further specified that the basket may be coated with a thin layer of gold.
Apparatus 2 (or type 2 apparatus) is essentially the same as apparatus 1 except that a paddle formed from a blade and a shaft is used as the stirring element rather than a basket. See FIG. 18. USP specifies as follows: the paddle conforms to the specifications shown in FIG. 2 thereof; the distance of 25±2 mm between the blade and the inside bottom of the vessel is maintained during the test; the metallic or suitably inert, rigid blade and shaft comprise a single entity; a suitable two-part detachable design may be used provided the assembly remains firmly engaged during the test; and the paddle blade and shaft may be coated with a suitable inert coating.
In testing, the dosage form is allowed to sink to the bottom of the vessel before rotation of the paddle is started. The USP further provides that a small, loose piece of non-reactive material such as a few turns of wire may be attached to dosage forms that would otherwise float and that other validated sinker devices may be used. Such devices may be formed of a material that is not easily corrodible by the dissolution medium, which may be acidic.
The testing procedure provided for in USP 25 <711> Dissolution is generally as follows. The stated volume of dissolution medium is placed in the vessel specified in the individual monograph for the drug being tested, the apparatus is assembled, and the medium is temperature equilibrated to 37° C.±0.5° C. (to approximate in vivo conditions). Thereafter, the dosage form is placed in the apparatus and the apparatus is operated at the rate specified in the individual monograph. Within the time interval specified, or at each of the stated times, a specimen is withdrawn from the vessel. Often the test is repeated in different vessels and/or with a second, third, or additional dosage form of the drug being tested.
Hence, it is known in the art to entrap dosage forms in a gold coated and/or stainless steel wire basket or in a few turns of non-corrosive wire. In addition, there are commercially available sinkers designed to hold a gelatin capsule in place in a USP 25 <711> Dissolution type 2 apparatus until it dissolves. Examples of commercially available capsule sinkers may be found at www.tabletdissolution.com. However, such devices are not designed to hold a tablet in a specific orientation during testing or to be used in conjunction with conventional dissolution baskets.
It is also known in the art to limit capsule movement during testing. Apparatus 7 of USP 25 <724> Drug Release teaches a holder designed for coated oral extended release tablets. See FIG. 19. Apparatus 7 specifies the use of a vertically reciprocating spring holder attached to a stainless steel tube and Sample Preparation A, USP 25 <724> Drug Release, allows for the use of a small nylon net bag at the end of a plastic rod. Such holders, however, have drawbacks. For example, the adhesive used to attach the tablets to the rod of the holder can compromise test results by affecting the rate-controlling coating and, thereby, the drug release profile. Additionally, such holders are not useful for tablets with a thin coating or shell because the coating or shell is likely to collapse and dump its content due to the upward and downward strokes of the holder during testing.
Finneran, U.S. Pat. No. 4,669,771, teaches a device for loosely holding a capsule during fluid immersion testing with a plurality of gripping fingers connected at one end which fingers surround a chamber to receive and retain a capsule. However, the device is not suitable for immersion testing of tablets. Fassihi, U.S. Pat. No. 5,412,979, teaches a disk that restrains a dosage form from floating to top of a fluid medium during testing using a vertical shaft and blade apparatus. However, the device is not designed to hold a dosage form in a specific orientation during testing or to be used in conjunction with a dissolution basket. In addition, it is known that differences in hydrodynamic effects corresponding to the relative position of test tablets in test vessels are likely to cause high variability in dissolution testing. See Study Highlights Flawed Dissolution Testing Procedure, Pharmaceutical Technology, October 2003, at 18–19.
The present invention provides a device and methods for immersion and dissolution testing whereby a tablet (by way of example, a controlled release tablet such as an osmotic tablet or matrix tablet) or capsule is held in a specific orientation or substantially fixed position during testing, which can advantageously provide test results that are more consistent between the different tablets (or capsules) and/or vessels used for the testing. For example, when a tablet begins to dissolve, the change in mass can result in a change in the orientation of the tablet either on the bottom of a dissolution vessel, or within a basket, if the movement of the tablet is not limited. A change in orientation of the tablet can result in variability of dissolution characteristics between different tablets of the particular drug being tested and/or vessels used for the testing.
The inventors have found the present invention is also well suited for use with tablets having a preformed passageway, e.g., laser drilled, such as an osmotic tablet with a semi-permeable membrane surrounding the tablet. If a tablet with a preformed passageway(s) reorients during dissolution testing, the test results may be altered if the reorientation interferes with diffusion of the medicament from the passageway(s). For example, if the tablet orients so that the passageway exit is at its bottom, the dissolved contents tend to “dump” out of the exit faster than if the exit is maintained at the top or side of the tablet. By maintaining the exit on the sides (if two exits) and/or on the side or top (if one exit), the contents are prevented from dumping, which allows a steadier rate of diffusion of the contents, including the active drug.
In addition, with respect to controlled-release dosage form tablets such as matrix tablets, the mass of the dosage form diminishes over time. Maintaining the orientation of such a tablet provides for a greater precision in results between different tablets of the particular drug being tested and/or vessels used for the testing.
The subject invention can also prevent tablets or capsules and their contents from sticking to the testing vessel. For example, as tablets dissolve, certain excipients, which may have adherent properties, can cause a tablet to adhere to the inner surface of the vessel. There is a high degree of variability in tablets that adhere to the vessel, which can also cause variability in dissolution between different tablets or capsules of the particular drug being tested and/or vessels used for the testing. By preventing such dosage form adhesion, the subject invention also can provide test results that are more accurate and/or consistent. The subject invention limits variability of location and orientation of tablets and capsules during dissolution testing, which also limits variation from vessel to vessel during testing.